Endothelial and Smooth Muscle Cell Contribution to Vascular Pathology

Our laboratory is interested in how endothelial cells and smooth muscle cells develop during embryogenesis and maintain a mature, functional vasculature. In addition, changes in the function of vascular cells occur in vascular disease, and we are interested in the control of disease-related phenotypic alterations. Our current focus is the function of the Notch signaling pathway in these processes.

Role of Notch Signaling in Vascular Homeostasis and Remodeling

Most blood vessels in adult organisms have a very low rate of cellular proliferation. The endothelium is a primary mediator of homeostasis, forming a contact-inhibited monolayer with tight cellular junctions. DLL4 is highly expressed in arterial endothelial cells, and plays a critical role in maintaining endothelial cell quiescence. Circulating bone morphogenetic proteins (BMP), BMP9 and BMP10 are additional quiescence signals that promote homeostasis in endothelial cells. With an intact endothelium, the smooth muscle cells also remain in a quiescent, contractile state, with high expression of smooth muscle cell markers. Vascular smooth muscle cells in the homeostatic condition express primarily Notch3. Once the vasculature achieves its mature conformation and function, constant communication between vascular cells is required to maintain homeostasis, and to respond to external stimuli such as cytokines, hormones, changes in blood flow or shear stress, inflammation, and mechanical trauma. In particular, endothelial cell communication with vascular smooth muscle cells is mediated via Notch signaling on adjacent cells; however, unique mechanisms including paracrine signaling via exosomes are emerging.

Examples of Notch signaling in vascular activation include angiogenesis and arteriogenesis after ischemia, pulmonary hypertension, vascular occlusive diseases such as atherosclerosis, and arteriovenous malformations. Our goal is to understand pathological Notch signaling to understand how it impacts the progression of vascular disease.